Cigarette smoking is the major causative factor for lung cancer. Primary prevention techniques must continue to take a prominent role in our efforts to reduce tobacco-related cancers. Since such efforts had only limited success in the past, complementary approaches are needed to control lung cancer. Chemoprevention constitutes a plausible approach, using synthetic or naturally occurring agents to inhibit preneoplastic events before the occurrence of clinically detectable cancer. Epidemiological and experimental studies indicate the benefits of the micronutrient selenium in cancer chemoprevention. However, the range between chemopreventive and toxic levels of inorganic selenium is narrow. We were the first to report that, in contrast to inorganic selenium compounds, synthetic organoselenium compounds were more effective and better tolerated in efficacy studies in several animal model systems (mammary, colon, liver). Recently, the efficacy of a representative synthetic organoselenium compound, 1,4- phenylenebis(methylene)selenocyanate (rho-XSC) has been extended to the tobacco-specific nitrosamine 4-(methylnitrosamino)-1 -(3-pyridyl)-1 - butanone (NNK)-induced lung tumors in A/J mice; rho-XSC inhibited DNA methylation in mouse and rat lungs. rho-XSC also inhibited thymidine kinase, protein kinase C, and protein kinase A in vitro and in several cell cultures. Our hypothesis is that dietary rho-XSC can block the metabolic activation of NNK and suppress tumor promotion and progression. To test our hypothesis and to mimic the western dietary pattern, we will use a high-fat diet in the proposed experiments. Specifically, our aims are: 1) Determine the chemopreventive efficacy of dietary rho-XSC on the initiation and post-initiation phases of NNK- induced lung tumorigenesis in A/J mice. In addition to efficacy studies, we will determine the effect of dietary rho-XSC on metabolism of NNK and the formation of DNA-adducts in mouse lung and liver. 2) Determine the chemopreventive efficacy of dietary rho-XSC on NNK- induced lung tumors in rats. Biochemical investigations will be carried out as described in Aim 1; the effect of dietary rho-XSC on adducts formation in relevant cell types of the lung will be determined. 3) Determine the effect of dietary rho-XSC on specific cytochrome P45O isozymes, transferases, hydrolases, and selenium-dependent glutathione peroxidase in the rat and mouse lung and liver. Priority will be given to those enzymes involved in the metabolism of NNK. 4) Determine the basis for the inhibitory effect of rho-XSC on protein kinase C utilizing selenium-77 nuclear magnetic resonance spectroscopy. We will test the hypothesis that the covalent binding of rho-XSC to -SH groups can disrupt protein structure and function. The results of this project will provide insights into the feasibility of using rho-XSC in future clinical trials on lung cancer chemoprevention.